GENETICS OF CORONARY THROMBOSIS

冠状动脉血栓形成的遗传学

• 批准号: 6527601
• 负责人: David Housman
• 金额: $ 31.27万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527601
• 关键词: anticoagulants; biological signal transduction; clinical research; clotting factor; coagulation factor IX; coagulation factor X; coronary occlusion /thrombosis; fibrinopeptide; genetic polymorphism; human subject; immunologic assay /test; protein C; prothrombin; vascular endothelium; zymogens

DESCRIPTION (Adapted from Applicant's Abstract) The hemostatic balance is regulated by vascular bed-specific endothelial cell signaling pathways. The applicants propose that coronary artery thrombosis arises through local alterations in one or more of these pathways. The overall goals of the Collaborative Program are to elucidate the molecular basis of endothelial cell subtype-specific gene expression in the heart and to identify the critical components of cardiac hemostasis. In this project , Dr. Rosenberg will study the role of a platelet-derived growth factor signaling pathway in mediating expression of a gene program within cardiac microvascular endothelial cells that includes tissue factor (TF). He will also optimize a recently developed mouse model of coronary artery thrombosis. In this project, Dr. Aird will examine the role of the Egr-l transcription factor in mediating cardiac-specific hemostasis. He will ask how a single gene can serve to "fine tune" hemostasis according to the local needs of the tissue. In this project, Dr. Mackman will evaluate the role of a thrombin-PAR-1 signaling pathway in governing local levels of procoagulant (TF) and fibrinolytic (tissue-type plasminogen activator) molecules within the heart. In addition, he will address the contribution of monocytederived TF to cardiac hemostasis. In this project, Dr. Housman will use genetic approaches in large populations to identify genotypes which significantly contribute to coronary thrombosis. The three basic science projects are interrelated by several common themes. Each component involves: (1) the study of a cardiac endothelial cell type-specific signaling pathway, (2) the determination of the effects of cell type-specific signaling pathways on global hemostasis (fibrin deposition) (3) the study of TF gene regulation and its role as the initiator of coagulation in the cardiac circulation, and (4) the use of transgenic mouse technology for studying vascular-bed specific hemostasis in the heart. The clinical project will serve as a vital link to validate the role of local hemostatic components in human populations.

描述（根据申请人的摘要改编） 止血平衡受血管特异性内皮细胞调节 信号通路。申请人提出冠状动脉血栓形成 通过其中一种或多种途径的局部变化产生。总体 协作计划的目标是阐明 内皮细胞亚型特异性基因在心脏中的表达并识别 心脏止血的关键成分。在这个项目中，罗森伯格博士 将研究血小板衍生的生长因子信号通路的作用 介导心脏微血管中基因程序的表达 内皮细胞包括组织因子（TF）。他还将优化 最近开发了冠状动脉血栓形成的小鼠模型。在这个项目中， AIRD博士将检查EGR-L转录因子在中介中的作用 心脏特异性止血。他会问一个单个基因如何用来“很好 根据组织的局部需求调音。在这个项目中，博士 麦克曼将评估凝血酶PAR-1信号通路的作用 管理局部凝聚剂（TF）和纤维蛋白水解的局部水平（组织类型 心脏内的纤溶酶原激活剂）分子。此外，他会 解决了单型TF对心脏止血的贡献。在这个 项目，Housman博士将使用大量人群中的遗传方法 鉴定基因型显着促进冠状动脉血栓形成。这 三个基础科学项目与几个常见 主题。每个组件涉及：（1）心脏内皮细胞的研究 类型特异性的信号通路，（2）测定细胞的影响 全局止血的类型特异性信号通路（纤维蛋白沉积）（3） TF基因调控及其作为凝结起始的作用的研究 在心脏循环中，（4）使用转基因小鼠技术作为 研究心脏中的血管膜特异性止血。临床项目 将作为验证局部止血成分的作用的重要联系 人口。